A new line of investigation is the pathogenesis of leukemia associated T(8;21) translocation which is present in 40% of a common subtype acute myeloid leukemia. This translocation fuses a portion of the AML1 gene of chromosome 21 to the ETO gene of chromosome 8, creating a new protein product called AML1/ETO. In current studies, the association of ETO with other nuclear proteins that regulate gene expression was studied using yeast two-hybrid method to identify ETO-binding proteins. For one clone, a 2.3 kb insert DNA was sequenced and revealed homology to murine nuclear receptor co-repressor. A variety of hormones and retinoic acids function as ligand-dependent transcription factors. Thus a novel human nuclear receptor co-repressor which binds to ETO proto-oncoprotein has been identified. Future studies will clarify the relationship between ETO and this protein and their role in the regulation of nuclear receptors and in leukemogenesis.